MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy

Ann Oncol. 2024 Jul;35(7):667-676. doi: 10.1016/j.annonc.2024.04.007. Epub 2024 May 3.

Abstract

Background: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor.

Patients and methods: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab.

Results: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002).

Conclusion: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Keywords: The Cancer Genome Atlas; avelumab; chemotherapy; endometrial cancer; next-generation sequencing.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Biomarkers, Tumor / genetics
  • Carboplatin / administration & dosage
  • Carboplatin / pharmacology
  • Carboplatin / therapeutic use
  • Class I Phosphatidylinositol 3-Kinases
  • DNA-Binding Proteins / genetics
  • Endometrial Neoplasms* / drug therapy
  • Endometrial Neoplasms* / genetics
  • Endometrial Neoplasms* / pathology
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunotherapy / methods
  • Microsatellite Instability*
  • Middle Aged
  • Mutation*
  • PTEN Phosphohydrolase / genetics
  • Paclitaxel* / administration & dosage
  • Paclitaxel* / therapeutic use
  • Progression-Free Survival
  • Transcription Factors
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • avelumab
  • Paclitaxel
  • Carboplatin
  • ARID1A protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Biomarkers, Tumor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • DNA-Binding Proteins
  • PIK3CA protein, human
  • Transcription Factors
  • Class I Phosphatidylinositol 3-Kinases